Abstract
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
MeSH terms
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Animals
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Cathepsins / antagonists & inhibitors*
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Cell Line
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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Models, Chemical
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Molecular Structure
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Structure-Activity Relationship
Substances
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1-(3-(4-(6-Chloro-2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl)propyl)-4,5,6,7-tetrahydro-5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo(4,3-c)pyridine
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Benzimidazoles
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Heterocyclic Compounds, 2-Ring
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Pyrazoles
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Pyridines
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Cathepsins
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cathepsin S